Replication-competent HIV-1 persists latently despite prolonged anti- retroviral therapy. Recent work has demonstrated that the lent reservoir decays with a mean t1/2 of 6.3 months in patients who consistently maintain plasma HIV-1 RNA levels<50 copies /ml. Slower decay rates occur in individuals who experience residual viral replication with intermittent episodes of plasma viremia. Viral persistence despite prolonged treatment is due not only to the slow intrinsic decay characteristics of residually infected cells but also the inability of current drug regimens to completely suppress HIV-1 replication in most patients. Minimal estimates of the total-body HIV-1 pool size, assuming an average total lymphocyte count of 10xe212, suggest that after 2-3 years of treatment, approximately one million to ten million cells harbor infectious virus. Given the slow intrinsic decay characteristics of residually infected cells, it follows that many years of effective treatment will be required to decreased levels to less than 1 infected cell. The practicality of this approach is limited by the difficulties inherent in multi-drug regimens that make years of therapy burdensome if not impossible for most patients . In the absence of an effective HIV vaccine, novel treatments need to be explored to accelerate the process of HIV-1 compartmental decay. Polyclonal immune activators have been suggested as a means of activating resting, memory CD4+ T lymphocytes, the major presumed reservoir of HIV-1 in patients after prolonged suppression of plasma viremia. As virus-producing cells have a limited lifespan, these agents may stimulate virus production and thereby hasten the death of HIV-1 infected cells while under antiviral coverage. Among individuals with low levels of viral replication, intensification of existing therapy with 1-2 additional anti-retroviral agents has been proposed. The goal of this proposal will be to design and implement novel immunologic and pharmacologic interventions and characterize their effect on viral burden during prolonged anti-retroviral therapy.